a minimalist introduction to (bio)organic chemistrykovacs/bioorg_intro_2d.pdf · a minimalist...

A personalview byLajosKOVÁCSUniversity ofSzegedHungary

A minimalist introduction to(bio)organic chemistry

TRIoH SymposiumFrankfurtMarch 23, 2005

Part 1: Basic conceptsPart 2: How does a chemist work?

How many compounds are known to date?

Substances registered in the Registry Database ofChemical Abstracts (1907-2005)

81,427,420 registeredorganic and inorganicsubstances andsequences(March 5, 2005)

person-years to draw one structure per minute

Structure(s)

PropertiesFunction(s)

Can you imagine akiss without lips?

Structures: the basic language of chemistry

an organic compound consists of a backbone (a relativelyunreactive, apolar carbon skeleton and the necessary

number of hydrogens) and the functional group(s)

Functional groups: polar atom or atom groups within a molecule that displaya characteristic combination of chemical and physical properties, e.g.:

alkenes

aromaticcompounds(arenes)

alcohols

amines(primary)

carboxylicacids

amides

Structures: dialects of a language

empirical formulas - 2D structural formulas - 3D structural formulas

Backbones and functional groups

the ensemble of functional groups and backbonedetermines the fundamental physical and chemical

properties of (organic) compounds e.g.

P aggregation state

P colour

P chemical reactivity

P acid-base character

Melting and crystallization: fats and oils

P natural fats are mixtures and

P crystallise in polymorphic forms

C16

C18

C18

average chain length (carbonatoms)

average number of doublebonds (per fatty acid residue)

lard

cocabutter

oliveoil

herringoil

cow’smilk fat

humanmilk fat

Melting and crystallization: the secrects ofa fine chocolate

increasing order

Crystal packing in triglycerides

33.8 C($-3)

A good chocolate melts in yourmouth but not in your hands...

Colour: beta-carotene

Chemical reactivity: determined mainly bythe functional groups

the distinction offunctional groups andbackbones issomewhat arbitrary

BUT...

Acid/base character: a key concept 1.

GMP

coloured groups involvedin protonation ordeprotonation

-logK = pK-log[H+] = pH0 < pH < 14

if [A- ]=[HA]then K = [H+]and pK = pH

Acid/base character: a key concept 2.

3.70

9.08

logD = lipophilicity(logP) in the functionof pH

lipid-soluble

water-soluble

Trifluoperazine (Stelazine)antianxiety, antiemetic,

antipsychotic drug

The shape of molecules: constitution

Hexane isomers (C6H14):

The shape of molecules: configuration

D-leucinesweet

L-leucineslightly bitter

When configuration matters: vision

The shape of the molecules: conformation

Fibroblast Growth Factor (FGF) acidic 1(102- 111, decapeptide, from bovine brain)

H-HisAlaGluLysHisTrpPheValGlyLeu-OH

An arbitrary conformation(solvent-accessible surfaceshown)

Crystal structure of the tyrosine kinase domain of fibroblast growth factorreceptor 1 in complex with su4984 inhibitor

"-helix$-turn

random coil

inhibitorcomplexed

The Holy Trinity

Structure(s)

PropertiesFunction(s)

P constitution

P configuration

P conformation

P aggregation state

P solubility

P elasticity

P colour

P chemical reactivity

P acidity/basicity etc.

P structural materials

P energy storage forms

P enzymes

P drugs

P fuels

P electronics etc.

Part 1: Basic conceptsPart 2: How does a chemist work?

Do I need to know this at all???

If you can manage alone...

...or in company

Areas of chemistry

P theoretical

P physical

P inorganic

P organic

P applied

P analytical

P structural

P environmental

P macromolecularetc.

P theoretical

P experimental

< synthetic (preparative)

< analytical

An iterative cycle

Synthesis design

Ppreparation of carbon framework and/or

P functional group manipulations(addition/interconversion/removal)

Pbuilding blocks< e.g. CambridgeSoft’s ChemACX Database:

690,463 commercially available products

A synthetic plan of Sildenafil (ViagraTM)

Tangram puzzles

The synthesis of Sildenafil (ViagraTM)

Purification: getting the right stuff

Pcrystallisation (crystalline substances)

Pdistillation (liquids)

Pchromatography (for the rest)< layer/column< atmospheric/forced flow< analytical/preparative

Structural elucidation: solving the puzzle

You need a propertool...

The tools

Pultraviolet spectroscopy (UV): unsaturated bonds(marginal role)

P infrared spectroscopy (IR): presence/absence offunctional groups

Pnuclear magnetic resonance (NMR): carbon/proton etc.framework (13C, 1H ...), fine structure (configuration,conformation)

Pmass spectrometry (MS): molecular weight,fragmentation

PX-ray: framework of heavy atoms in solid state(configuration, conformation)

Instruments, instruments...

How much time does this take?(Optimistic estimates)

days to weeks

days to weeksper step

days to weeksper step

days to weeksper step

days toweeks

percompound

but...

P availability ofbuilding blocks

P stereoisomers

P scaling-up problems

P reproducibility

P multistep syntheses

P yields

P timing etc.

...the preparation of a new compound in reasonable amount in amultistep synthesis involving new reaction(s) may easily take a year!

Just too slow?

but...

P for delicate objectsyou need chisels nota chain-saw

Speeding up the synthesis

(An arbitrary selection of currently available methods)

Psolid phase synthesis< oligomers (peptides, nucleotides), small molecules

Pcombinatorial and parallel synthesis< lead optimisation

Pmulticomponent reactions< shortening reaction pathways

Pmicrowave activation< accelerating reactions

Pmetathesis reactions< synthesising complex frameworks etc.

Solid phase synthesis of Sildenafil (ViagraTM)

but... P complicated reagents

P small-scale synthesis

Biginelli reaction

conventionalheating

microwaveheating

but...P you need a suitable reaction to speed up...

Multicomponent reactions & microwave activation

Accelerating the purification 1.UPLC (Ultra Performance Liquid Chromatography, Waters)X-LC (Extreme High Pressure Liquid Chromatography, Jasco)

particle size (:m)

pressure applied (bar)

HPLC UPLC

5-10 < 2

400 1,000-7,500

UPLC (right) separates many more components outof urine samples than does conventional HPLC (left)

A prototype UPLCinstrument

but you needsome cash...

Accelerating the purification 2.OPLC (Overpressurised Layer Chromatography/Optimum Performance Laminar Chromatography, OPLC-NIT/Bionisis)

P forced-flow (50 bar) planar chromatography (acombination of TLC and HPLC)

P simultaneous multi-sample processing (up to 70)

P fast separation (av. 10 to 20 min)

P low solvent consumption (< 5mL/run)

P analytical and preparative (0.2-20 mg)

separation of xanthines(caffeine, theophylline,theobromine) in tea

but you needsome cash...

Picture credits 1.P blacksmith shop: http://www.anvilfire.com/home/images/slideshow/g_fahrenwald/blacksmith_shop_1.htm

P iceberg: http://en.wikipedia.org/wiki/Image:Iceberg.jpg

P lips and mouths:< http://www.portrait-artist.org/ basics/shading.html< http://www.kristoffer.com/temp/Lips.jpg< http://drake.marin.k12.ca.us/students/jollyn/portfolio/sketcheshtm.htm< http://www.africa.upenn.edu/faminefood/images/Hankalta%20eating%20fruit.jpg< http://www.public.asu.edu/~atjlb/FOOT%20IN%20MOUTH.JPG< http://world.std.com/~damned/Wendy/Pix/kiss.jpg

P bones: http://www.arch.soton.ac.uk/Research/CAAA/bones/pompeii2.htm

P dog skeleton: http://www.wolfshadow.co.uk/Dog%20skeleton.jpg (edited)

P figures on fats and oils:< T. P. Coultate: Food. The chemistry of its components. Royal Society of Chemistry, Cambridge, 2002, p. 104-

109.< http://www.public.asu.edu/~mmcbeath/mcbeath.links/links.html

P beta-carotene UV spectrum: http://omlc.ogi.edu/spectra/PhotochemCAD/html/beta-carotene.html

P colour spectrum: http://www.city.ac.uk/colourgroup/spectrum.gif

P pK and logD predictions: http://www.chemaxon.com/marvin/sketch/demo.html

P amino acid enantiomers: http://web99.arc.nasa.gov/~astrochm/aachiral.html

P FGF inhibitor complex: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1AGW

Picture credits 2.P bikes:< http://www.intellectualpoison.com/Pics/invertedunicycle.jpg< http://www.spicyjoke.com/unicycle.html< http://www.sneltweewielers.nl< http://www.kitepower.com/welcome.html

P tangrams: http://www.bilet.go.ro/origami/origami9.htm

P instruments:< http://www.laserglass.com.cn/measuring%20Instrument.htm< http://www.varianinc.com/image/vimage/docs/corp/businesses/nmr/shared/probe.jpg< http://ncbr.chemi.muni.cz/PICTURES/EQUIPMENT/500MHz.jpg< http://en.wikipedia.org/wiki/Image:Pacific_Northwest_National_Laboratory_800_MHz_NMR_Spectr

ometer.jpg< http://www.physics.utoronto.ca/ ~isotrace/specv01.htm

P wooden statue: http://www.godstatues.com/ wooden-statues-antique.html

P chisels: http://www.woodworking-tool-store.com

P black and white pictures on logging and cameras by Darius Kinsey (1869-1945), e.g.:http://content.lib.washington.edu

P temperature profile of microwave heating: Angew. Chem. Internatl. Ed. Engl. 43, 6250-6284 (2004)

P UPLC: http://pubs.acs.org/isubscribe/journals/cen/82/i47/ html/8247sci3.html?emFrom=emLogin

P OPLC chromatogram: courtesy of Dr. E. Mincsovics (OPLC-NIT Ltd, Budapest)

P cash sack: http://sidereus.org/MONEY/money_dollar_cash-2.htm